Powder compartment for high dosage drug delivery

ABSTRACT

A dry powder inhaler for pulmonary or nasal use, comprising at least an inhaler body  801  and a cartridge  803  with at least one powder compartment  805  including one dose of a drug. The body has an opening  804  shaped for receiving the cartridge  803  and the means to allow a controlled sliding movement of the cartridge  803  relative to the body  801  after mounting. The cartridge powder compartment  805  comprises at least two inlets or slits  806, 809 , at least one of which is a side inlet  809 , for the admission of air, and a compartment outlet  807  to allow filling and fluid communication with an inhalation channel  808  provided in the body  801 . In use, the patient slides the cartridge  803  relative to the body  801  from the storage position, where the inlets in the cartridge powder compartment  805  are blocked and sealed by walls comprised in the body  801 , into the inhalation position, where the compartment inlets become available for the admission of air used in the dispersion of the particles there contained and the compartment outlet  807  becomes aligned with the inhalation channel  808  in the body  801  to allow the entrainment of the dose dispersed through the device and into the desired site of action during inhalation. The addition of one or more lateral vents  809  in the cartridge powder compartments induces a turbulent and swirling flow pattern that promotes improved dispersion and entrainment. The invention affords a very economical and simple device for the delivery of high dosages of inhaled medicines.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention describes a novel powder compartment for asingle-use disposable pulmonary or nasal inhaler of simple construction,operation and low cost for the delivery of high dosages ofpharmaceutical compounds.

Inhalers used for the delivery of pharmaceutical compounds have becomewidespread and include pressurized metered dose, nebulizers andpowder-based inhalers. The latter category delivers the dose ofmedicinal powder using the energy generated by the patient's inspiratoryeffort and includes multi-use reservoir-based devices, re-usable devicessupplied with unit-doses packaged in blisters, re-usable devices usingunit-dose capsules loaded by the patient, and single-use disposablepowder-based inhalers. The present invention is in this last category.

Powder-based inhalers have been used mainly for maintenance treatment ofrespiratory diseases such as asthma or the chronic obstructive pulmonarydisease. However, single-use disposable devices have deservedconsiderable attention due to the need to treat situations were aninfectious agent is being treated or is present in the mouth or airwaysand the elimination of the potential for inhaler contamination is thusrequired.

Furthermore, the effort to develop single-use disposable inhalers hasalso been fuelled by the growing interest in delivering to patients highpayloads, in the range of 50 to 120 mg, of pharmaceutical compounds suchas antibiotics, vaccines, proteins, peptides, insulin or other drugssystemically via the lung or nose through few, simple and intuitiveinteractions with the device. In such applications, pharmaceuticalcompounds that have been particle engineered by processing techniquessuch as spray drying or jet milling are normally characterized by highadhesion and cohesion properties resulting from low median particle sizeby volume, typically below 2 μm, in addition to low bulk density,typically in the range of 0.2 g/cm3-0.5 g/cm3.

Therefore, a major challenge is designing the mechanism for aerosolizingand dispersing large quantities, in the range of 50 to 120 mg, of highlycohesive and adhesive powders while minimizing the amount of powderretention in the device. In addition, a significant challenge is alsothe provision of deagglomeration mechanisms which ensure the break-up ofsuch large quantities of highly agglomerated drug particles down toparticles with an inhalable size of less than 5 μm while,simultaneously, preventing such large dose to be released in a veryshort period of time. Such sudden release may lead to the “powderymouth” effect, throat irritation and large drug losses in the upperairways. The means for powerful aerosolisation and controlled powderdeagglomeration and release is thus required by design.

Furthermore, the great majority of the patients requiring antibiotics,vaccines, proteins, peptides or other drugs in such applications areinhaler-naive and may not have any training in inhalation. It is thusrequired that the device be of extreme simplicity and intuitive to use.In addition, the developer of a disposable inhaler for high dosage drugdelivery is also faced with the challenge of gaining competitiveadvantage through a reduction in the cost of the device, both throughthe use of the fewest number of components as possible and designing forfast assembly during high volume manufacturing.

2. Discussion of Prior Art

There is abundant prior art in the field of single-use disposableinhalers, but a disposable inhaler solving all the above requirementshas not been provided yet. The present application is particularlydirected at the inventive improvement of the inhaler described inPT103481.

Previously, as described in PT103481 and illustrated in FIG. 1a to 1cand 2a of the accompanying drawings, there was known a disposableinhaler comprising a body 101 including a mouthpiece 102 and a cartridge103 mounted in an opening 104 provided in the body 101 and having atleast one powder compartment 105. The powder compartment 105 had inletholes 106 to admit air and outlet holes 107 to communicate with aninhalation channel 108 provided in the body 101. Furthermore, thecartridge 103 was made slidable relative to the body 101 by the patient,between a first position detailed in FIG. 1a where the compartment rearholes 106 were isolated and sealed, and a second position detailed inFIGS. 1b and 1c in which the compartment rear 106 and front 107 holeswere aligned with the body inhalation channel 108, thus allowing theflow of air to disperse and entrain the powder through the mouthpieceand into the patient's mouth or nasal cavity and finally into thedesired site of action. The construction disclosed in PT103481 allowedfor a device with pre-filled unit doses of powder for patientconvenience, disposable for reasons of safety and hygiene, simple foreconomic reasons and intuitive for ease of use by the patient. Whilethis inhaler is being successfully marketed, tests indicate the maximumdeliverable dose is in the region of 10-20 mg of powder.

Other single-use disposable inhalers are also already known in the priorart.

U.S. Pat. No. 5,797,392 discloses one of the simplest designs of asingle-use disposable inhaler similar to a drinking straw. Althoughsimple, the construction disclosed does not provide dispersion anddeagglomeration mechanisms or features allowing the break-up of largequantities of highly cohesive drug particles and excipients down to theinhalable size while minimizing powder retention in the device.

U.S. Pat. Nos. 5,042,472, 5,239,991, 6,098,619 and WO pat. 2014/175815disclose also other simple single-use and disposable devices apparentlyabsent of major powder deagglomeration features and the constructionsdisclosed in the drawings are likely to cause the sudden release ofpowder leading to the undesirable “powdery mouth” and throat irritationeffects.

U.S. Pat. Nos. 6,286,507, 2008/0190424 and US pat. 2009/0250058 discloseother single-use disposable inhaler constructions generally comprising afirst body member including a powder compartment and a second bodymember which are closely fit to form an inhaler body with an outlet,where the two body member are separated by a strip or tape which exposesthe powder compartment to air when pulled away from the inhaler body.However, the constructions presented rely on simple throughflows thatare absent of flow patterns into the powder compartment thus preventingthe application of powerful dispersion and deagglomeration forces onpowders for its effective detachment from the compartment's walls, whichis particularly important for the successful delivery of large payloadsof cohesive powders.

U.S. Pat. No. 6,941,947 discloses another single-use dry powder inhalerhaving a dispersion chamber, a blister supported and adjacent to thedispersion chamber, a mouthpiece and a hinged cover. The openingmovement of the hinged cover causes the blister to open and an airflowpath is formed that extends under the blister and into the dispersionchamber. However, the drawings disclosed in this patent show also anapparent absence of powerful flow patterns for dispersion anddeagglomeration of large payloads of powder, a construction comprisingat least 4 unique components and a non-trivial assembly sequence, bothadding to total manufacturing cost.

There is therefore the need for a single-use disposable device whichachieves the functionalities of the disposable inhalers described abovewith effective aerosolisation and deagglomeration mechanisms for largepayloads of very cohesive powers, in the range of 50 to 120 mg, thatminimizes powder retention, that is simple and intuitive to use and thatcan be manufactured at a very low cost.

SUMMARY OF THE INVENTION

The present invention seeks to provides a novel powder compartment for adisposable inhaler that improves the construction disclosed in PT103481for the dispersion and deagglomeration of large payloads, in the rangeof 50 to 120 mg, of inhalation powders characterized by high cohesiveand adhesive properties, resulting from a low median particle size byvolume, typically below 2 μm, while maintaining an inhaler that issimple and intuitive to use and that can be manufactured at a very lowcost. Furthermore, the present invention seeks to provide a powdercompartment for a disposable inhaler that minimizes the powder retentionin the device during the dispersion of large powder payloads whileretaining an improved deagglomeration performance leading to animprovement of the dose delivered to the patient's respiratory system.

When testing with a high payload, in the range of 80 to 100 mg, ofinhalable amorphous composite particles composed of 80% trehalose and20% leucine produced by spray drying, used as model drug particlesrepresentative of the typical high cohesive-adhesive behaviour found inpowders for high dosage applications, we initially scaled up theexisting construction disclosed in PT103481. This scale-up was madelinearly in every dimension by 20% to increase the powder compartmentcapacity for accommodating such payloads of powders with typical bulkdensity in the range of 0.2 g/cm3-0.5 g/cm3. However, at a pressure dropof 4 kPa, the emitted mass from the device calculated from the mass ofpowder deposited at each stage of a cascade impactor was about 50%. Itwas clear that dispersive and aerosolisation characteristics of anenlarged construction as disclosed in PT103481 were not going to lead toan effective large dose disposable inhaler.

Subsequently, in order to increase the dispersive and aerosolisationpower of the construction disclosed in PT103481, additional symmetricalair vents providing supplementary air flow to the powder compartmentwere introduced and the new construction was tested with the samepayload of the model drug particles. At a pressure drop of 4 kPa, theemitted mass from the device calculated from the accumulated mass ofpowder deposited at each stage of a cascade impactor was increased toapproximately 65% of the nominal or starting dose. This performance wasstill not adequate and it was clear that just an increase of flow ratepassing through the powder compartment, provided by symmetricallydisposed air vents was not going to lead to an effective large dosedisposable inhaler.

The inventive solution was given by placing the air vents in adisposition that maximizes turbulence and aerosolization, in a newgeometry. The powder compartment disclosed in PT103481 needed to bereinvented to create novel, effective dispersive and aerosolisationdynamics leading to low powder retention and a disposable inhalercapable of operating with large payloads of powders characterized bychallenging cohesion-adhesion properties. To attain such purpose, theexisting powder compartment which was provided with a an air slit at thebottom and a large outlet at the top, was constructed with additionallateral vents, forming pairs of lateral vents, placed at various heightsof the powder compartment, with each vent forming the pair of ventsoffset relative to each other to provide a non-tangential admission ofair. The new construction was tested with the same payload of the modeldrug particles representative of high dosage applications. At a pressuredrop of 4 kPa, the emitted mass from the new device calculated from themass of powder deposited at each stage of a cascade impactor wasapproximately 91% and powder retention within the compartment itself wasobserved to be residual. The results indicate that the novel design ofthe powder compartment provides a high rate of drug delivery ofchallenging powders characterized by low density and highcohesive-adhesive properties.

The table data indicates the improvement in performance in gravimetricemitted dose, expressed in percent of emitted dose, and the variabilityof performance expressed in terms of percent relative standarddeviation.

Body bottom Emtitted inhalation Emitted Mass Powder compartment channelinlet Mass (%) RSD (%) Scale-up PT103481 Multiple orifices, 51.0 44.8 3× 3 grid arrangement Scale-up PT103481 with Multiple orifices, 69.0 29.3additional symmetrical air 3 × 3 vents grid arrangement Scale-upPT103481 with Single orifice 80.5 5.2 additional symmetrical air ventsScale-up PT103481 with Multiple orifices, 85.0 5.4 additionalsymmetrical air 2 × 2 vents grid arrangement Scale-up PT103481 withMultiple orifices, 91.2 1.4 additional air vents in 3 × 3 offset gridarrangement Scale-up PT103481 with Single orifice 88.5 4.3 additionalair vents in offset Scale-up PT103481 with Multiple orifices, 92.9 1.1additional air vents in 2 × 2 offset grid arrangement

The present invention accordingly provides a dry powder inhaleraccording to claim 1.

More particularly, the inhaler of the present invention comprises twoplastic-injected components as in PT103481: a body and a cartridge. Thebody and cartridge are locked together after assembly to form anintegral and functional inhaler.

As in PT103481, the inhaler body is provided with a mouthpiece ornosepiece, an opening shaped for receiving and holding in place acartridge and an inhalation channel for providing fluid communicationbetween the patient's mouth or nose when engaged with the mouthpiece ornosepiece and the assembled cartridge. One or more body side inlets areprovided to admit air directly from the atmosphere to the inhalationchannel. Optionally a body bottom opening is included in the bottom wallof the body opening shaped for receiving the cartridge, to allow theadmission of air from the atmosphere into the cartridge powdercompartment when the cartridge is moved into the inhalation position.One or more rails are also provided in the side walls of the bodyopening shaped for receiving the cartridge where one or more pins of thecartridge engage to provide the means for allowing the sliding movementof the cartridge relative to the body and limit its sliding travel.

As found in PT103481, the cartridge includes at least one powdercompartment, preferably two, that are built or moulded therein, whichare always isolated from each other and are of tapered cylindrical ornear-cylindrical shape with rounded extremities absent of sharp angles,such as spherical, oval and the like to minimize powder retention duringand after inhalation. The cartridge comprising the powder compartmentsis made movable when mounted in the body opening. This movement isallowed through the engagement of one or more cartridge pins with therails provided in the body which allow the controlled sliding of thecartridge relative to the body. In addition, there is at least onecompartment bottom slit for the admission of air that is of very smallsize, between 0.1 and 2 mm in width, preferably 1 mm or less in width,and is tapered in the direction of the compartment to create a funnelthat blocks the flow of powder under gravity and other forces. Eachpowder compartment comprised also a compartment outlet, normally of thesame or similar diameter as the compartment itself, to allow normalfilling and automated high-speed filling of the powder and to allowfluid communication with the body inhalation channel through the bodybottom inhalation channel inlet when the cartridge is moved into theinhalation position.

However, the inhaler of the present application includes new featuresnot found in the inhaler described in PT103481 or in the prior art andthey are now detailed.

In this new inhaler, the cartridge powder compartment further comprisesat least two compartment vents for the admission of air, at least one ofwhich is a lateral vent, preferably two or four forming pairs of lateralvents being present, where each of said pairs is included in oppositeends of the powder compartment and each vent forming the pair is offsetrelative to the other to provide a non-tangential admission of air, andbeing the lateral vents of very small size, between 0.1 and 2 mm inwidth, preferably 1 mm or less in width, to minimize powder leakageunder vibration or other forces. The or each side vent preferably tapersinwards towards the inner surface of the compartment wall so as tofunnel the air as it is drawn through the vent into the compartment,thereby increasing aerodynamic efficiency and facilitatingmanufacturing.

Furthermore, the new cartridge powder compartment comprises at least onecompartment protruding rim or similar construction that provides closemechanical contact and interference with the top or bottom walls, orboth, of the body opening shaped for mounting the cartridge, and atleast one pair of compartment protruding rims or similar construction atthe side inlets that provides close mechanical contact and interferencewith the side walls of the body opening shaped for mounting thecartridge, to ensure sealing of the powder compartment while allowing alow frictional sliding movement of the cartridge.

Two additional features are found in the inhaler of the presentinvention which are not present in the inhaler of PT103481. One is thatthe inhaler body of the present invention further comprises a bottominhalation channel inlet, included in the top wall of the body openingshaped for receiving the cartridge, where said bottom inhalation channelinlet comprises a single orifice or multiple orifices of any shape ormultiple orifices of any shape arranged to form a structured grid, thatjointly provide a sharp geometric constriction in the fluid channelpassage area where the geometric constriction area ranges between 0.3and 0.99 of the cartridge powder compartment outlet cross section area,preferably between 0.8 and 0.98.

The other additional feature in this new inhaler is that the inhalerbody includes one or more body side openings, included in the side wallsof the body opening shaped for receiving the cartridge, to allow theadmission of air from the atmosphere into the cartridge powdercompartment when the cartridge is moved into the inhalation position.

The inhaler body and the cartridge can be made by injection-moulding ofany suitable material for pharmaceutical use such as polyethylene (PE),polypropylene (PP), polysulfone (PSU), acrylonitrile butadiene styrene(ABS), polymethylmetacrilate (PMMA), polycarbonate (PC), polypropileneoxide (PPO), polybutylene terephthalate (PBT) polyethylene terephthalate(PET), liquid crystal polymer (LCP), polyethyleneimine (PEI),polyphenylenesulphide (PPS). Material selection should be made tomaximize compatibility with the powder to be contained and delivered,minimize retention during inhalation and degradation during storage andallow transparency if possible.

During assembly, after filling the cartridge powder compartments with aunit dose of powder, the cartridge is inserted into the body through theopening shaped for mounting the cartridge. The powder compartment entersinto the contact with the top, bottom and side walls of the body openingproviding a close fit and sealing of the compartment. In addition, whenthe cartridge is mounted the pins engage with the body rails and allowthe sliding movement into the cartridge storage position.

In the storage position, the powder compartments are offset relative tothe inhalation channel provided in the body. Furthermore, the powdercompartment bottom inlet slits are in contact with and fully blocked bythe bottom wall of the body opening for mounting the cartridge. Inaddition, the powder compartment lateral vents are in contact with andfully blocked by the side walls of the body opening for mounting thecartridge. Therefore, the powder unit dose is effectively sealed insideits compartment and close contact with the opening bottom and side wallsprevents the powder compartment contents from escaping. In its storageposition, the inhaler is then ready for packaging, desirably in a foilor aluminium pouch, or pouch or packaging of any other suitable materialand under low or equilibrium humidity conditions.

During use of the inhaler of the present invention, the patient removesit from its packaging and accesses the inhaler with the cartridge in thestorage position. The patient then pushes into the cartridge to slide itinto the inhalation position. At this position, the powder compartmentbottom inlet slit becomes aligned with the air inlet provided in thebottom wall of the body opening for allowing air admission. Furthermore,at this position, the powder compartment lateral vents become alignedwith the side openings/windows provided in the side walls of the bodyopening for allowing air admission. Also, at this position, the powdercompartment outlet becomes aligned with the bottom inlet of theinhalation channel that is included in the top wall of the body opening.

When the cartridge has traveled into the inhalation position, thepatient then inhales a first dose, according to the instructions foruse, and airflow is created across the device. Air is first able travelthrough the body bottom air inlet and into the powder compartmentthrough the compartment bottom inlet slit effectively inducing aturbulent jet to disperse the particles there contained.

In addition, air is also able to travel through the body sideopening/window into the powder compartment through compartment lateralvents or through the pair of compartment lateral vents, which provideadmission of supplementary air to allow an increase in the turbulencekinetic energy within the compartment that is available for dispersionand deagglomeration of the drug particles. Moreover, the non-tangentialair admission through the compartment lateral vents induces a turbulentvortex that confines the bottom turbulent jet and generates a highvelocity magnitude near to the compartment walls and thus provide themeans to effectively reduce powder retention in the device duringinhalation.

The turbulent and swirling air flow generated in the compartment thusallows the particles to be dispersed and travel through the powdercompartment outlet and into the bottom inhalation channel inletcomprised in the body. There, the sudden cross sectional reduction thatis constructed through the body inhalation channel inlet design allowsfurther deagglomeration and break-up of the particle clusters throughimpaction on the surrounding inlet walls and through the generation ofhigh shear forces and turbulence kinetic energy across the inlet passageitself.

The flow of air with entrained particles then enters the body inhalationchannel and the supplementary air flow provided through the body sideinlets induces additional channel turbulence leading to furtherdispersion and deagglomeration of the particles, for entrainment andfinal deposition in the intended site, in the lung or in the nasalcavity, depending on the application. If there is a second powdercompartment comprised in the cartridge, the patient then moves it to theinhalation position and inhales a second time, repeating the maneuver asoften as there are compartments. A benefit of all of these inlets andlateral vents is that inhalation may be complete with one singleinhalation attempt.

In addition to providing the turbulent kinetic energy for powderdispersion and deagglomeration, the inlets, slits and vents provided inthe powder compartment as well as those in the body allow the design ofthe inhaler resistance and aerodynamic profile which in turn determinesthe comfort experienced by the patient during inhalation.

This novel construction allows the dispersion and deagglomeration oflarge payloads of cohesive inhalation powders while minimizing powderretention and while maintaining an inhaler that is simple and intuitiveand maintaining the part count to two unique components assembledthrough a single and simple assembly step, both contributing to lowmanufacturing cost and consequent economic advantage.

Based on these advantages, it is one inventive feature of the presentapplication that the cartridge powder compartment of tapered cylindricalor near-cylindrical shape comprises at least one bottom inlet slit andat least one side/lateral vent, preferably two or four forming pairs oflateral vents, which are respectively blocked and sealed by the bodyopening bottom and side walls when the cartridge is in the storageposition, and which become available for the admission of air into thecompartment when the cartridge is aligned and placed into the inhalationposition.

It is also an inventive feature of the present application that thecartridge powder compartment lateral vents are included in oppositesides of the powder compartment and each vent forming one pair is offsetrelative to the other to provide a diagonal, non-tangential admission ofair, thus providing the means for the admission of supplementary airflow inducing a turbulent vortex in the compartment that increases theturbulent energy available for the dispersion and deagglomeration ofdrug particles there contained, and that increases the near-wallvelocities in the compartment for the reduction of powder retentionduring inhalation.

It is also an inventive feature of the present application that thecartridge powder compartment lateral vents are of very small size,between 0.1 and 2 mm in width, preferably 1 mm or less in width, toincrease air vent velocities for the application of high dispersiveforces on particles there contained, and are further tapered towards theinner surface of the compartment to increase aerodynamic efficiency andallow manufacturing through standard injection moulding processes.

It is also an inventive feature of the present application that thecartridge powder compartment has at least one pair of compartmentprotruding rims or similar construction at the side inlets that providesclose mechanical contact and interference with the side walls of thebody opening shaped for mounting the cartridge, to ensure sealing of thepowder compartment while allowing a low frictional sliding movement ofthe cartridge.

It is also an inventive feature of the present application that the bodyinhalation channel comprises a bottom inlet included in the top wall ofthe body opening shaped for receiving the cartridge where said bottominhalation channel inlet comprises a single orifice or multiple orificesof any shape or multiple orifices of any shape arranged to form astructured grid, that jointly provide a sharp geometric constriction inthe fluid channel passage area where the geometric constriction arearanges between 0.3 and 0.99 of the cartridge powder compartment outletcross section area, preferably between 0.8 and 0.98, that allows furtherdeagglomeration and break-up of the particle clusters dispersed withinthe powder compartment through impaction on the surrounding inlet wallsand through the generation of high shear forces and turbulence kineticenergy across the inlet passage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1a to 1 c and 2 a show a prior art inhaler;

FIGS. 2b to 2g show perspective and side views of multiple embodimentsof the powder compartment according to the invention;

FIG. 3a shows a longitudinal sectional detailed view of the cartridgepowder compartment outlet when the cartridge is moved into theinhalation position of and body inhalation channel bottom inletaccording to the invention;

FIG. 3b to 3d show top views of multiple embodiments of the bodyinhalation channel bottom inlet according to the invention;

FIG. 4a to 4b show perspective views of the inhaler according to theinvention when the powder cartridge is respectively in the storage andinhalation position;

FIG. 5a shows a longitudinal sectional view of the inhaler according tothe invention when the powder cartridge is in the storage position;

FIG. 5b shows a longitudinal sectional detailed view of the powdercartridge bottom inlet according to the invention when the cartridge isin the storage position;

FIG. 5c shows a transversal sectional view of the inhaler according tothe invention when the powder cartridge is in the storage position;

FIG. 6a shows a longitudinal sectional view of the inhaler according tothe invention when the powder cartridge has been moved into theinhalation position;

FIG. 6b shows a longitudinal sectional detailed view of the powdercartridge bottom inlet according to the invention when the cartridge hasbeen moved into the inhalation position;

FIG. 6c to 6d show transversal sectional detailed views of the inhaleraccording to the invention when the powder cartridge has been moved intothe inhalation position;

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings, numbered sequentially after the word “FIG.”,like numerals indicate like parts, and each of the embodiments isidentified with series of numbers where the number of hundreds is thenumber of the embodiment (1xx to 8xx) and the equivalent feature in eachof the embodiments has the same number xx.

Referring to FIG. 2 which shows multiple embodiments of the powdercompartment according to the invention, there is shown in FIG. 2a thefirst embodiment of the cartridge powder compartment 105 of taperedcylindrical or near-cylindrical shape comprising at least one bottominlet slit 106. FIG. 2b shows a second embodiment of the cartridgepowder compartment 205 of tapered cylindrical or near-cylindrical shapeaccording to the invention comprising one bottom inlet slit 206 and atleast one lateral vent 209. FIG. 2c shows a third embodiment of thecartridge powder compartment 305 according to the invention comprisingone bottom inlet slit 306 and a pair of compartment lateral vent 309included in opposite sides of the powder compartment 305. FIG. 2d showsa fourth embodiment of the cartridge powder compartment 406 according tothe invention comprising one bottom inlet slit 406 and a pair ofcompartment lateral vent 409 included in opposite sides of the powdercompartment 405 where each lateral vent 409 forming the pair islongitudinally offset relative to the other to allow a non-tangentialadmission of air into the powder compartment 405. FIG. 2e shows a fifthembodiment of the cartridge powder compartment 505 according to theinvention comprising one bottom inlet slit 506 and a pair of compartmentlateral vent 509 included in opposite sides of the powder compartment505 where each lateral vent 509 forming the pair is longitudinally andvertically offset relative to the other to allow a diagonal andnon-tangential admission of air into the powder compartment 505. FIG. 2fshows a sixth embodiment of the cartridge powder compartment 605according to the invention comprising one bottom inlet slit 606 andmultiple pairs of compartment lateral vent 609 included in oppositesides of the powder compartment 605 where each lateral vent 609 formingone of the pairs is longitudinally and vertically offset relative to theother to allow a diagonal and non-tangential admission of air into thepowder compartment 605. FIG. 2g shows a seventh embodiment of thecartridge powder compartment 705 according to the invention comprisingmultiple pairs of compartment lateral vent 709 included in oppositesides of the powder compartment 705 where each lateral vent 709 formingone of the pairs is longitudinal and vertically offset relative to theother to allow a diagonal and non-tangential admission of air into thepowder compartment 705.

FIG. 3a shows a detailed longitudinal sectional view of the powdercartridge 203 including a powder compartment 205 according to theinvention when the cartridge 203 is moved into the inhalation positionand is aligned with a body inhalation channel 208 which allows the fluidcommunication between a powder compartment outlet 207 and a bodyinhalation channel bottom inlet 210 included in a top wall 211 of a bodyopening 204 for receiving the cartridge 203. There is also shown in FIG.3a that the inhalation channel bottom inlet 210 comprises one or moreorifices included in the top wall 211 of the body opening 204 thatjointly provide a sudden geometric obstruction of the channel passagearea in relation to the powder compartment outlet 207 cross sectionalarea. Moreover, FIGS. 3b to 3d show top views of additional embodimentsof the inhalation channel bottom inlet 210, each similarly providing asudden obstruction of passage area in relation to the powder compartmentoutlet 207 cross section area. FIG. 3b shows an embodiment of theinhalation channel bottom inlet 310 comprising a single circularorifice, while FIG. 3c shows an embodiment including an inhalationchannel bottom inlet 410 formed of multiple circular orifices. FIG. 3dshows an embodiment of an inhalation channel bottom inlet 510 formed ofmultiple orifices with non-circular shape. FIG. 3e further depicts anembodiment of an inhalation channel bottom inlet 610 comprising multipleorifices forming a structured grid.

Referring next to FIGS. 4, 5 and 6, there is shown an inhaler embodimentaccording to the invention in two different operational configurations.In FIG. 5a , a powder cartridge 803 is assembled into an opening 804shaped for receiving it in the body component 801 and the cartridge 803is the storage position. As shown in detail in FIGS. 5b and 5c , whenthe powder cartridge 803 is in it storage position, a compartment bottominlet slit 806 is closed by smooth bottom walls 812 of the body opening804 and a powder compartment lateral vent 809 is closed by themechanical interference between compartment side protruding rims 813 andsmooth side walls 814 of the body opening 804 so that the powder isblocked inside the compartment 805.

In FIG. 6a , the powder cartridge 803 has been moved from the storageposition shown in FIGS. 5a to 5c to the inhalation position allowing oneof the powder compartments 805 to become aligned with the bodyinhalation channel 808. In this position. FIG. 6b details that airadmission is allowed from atmospheric conditions through a body bottomopening 815 shaped in the body bottom walls 812 into the powdercompartment 805 through the compartment bottom inlet slit 806. Also inthis position, FIG. 6c shows in detail that supplementary air admissionis also allowed from atmospheric conditions through the body sideopening window 816 shaped in the body side walls 814 into the powdercompartment 805 through the compartment lateral vent 809. Furthermore,FIG. 6a shows also that when one of the powder compartments 805 is movedinto the inhalation position, fluid communication is established betweena powder compartment outlet 807 and a body inhalation channel 808through the body inhalation channel bottom inlet 810, which provides asudden reduction of passage area relative to the powder compartmentoutlet 807 cross section area as depicted in FIG. 6 a.

When the powder cartridge 803 is in the inhalation position and thepatient's mouth or nose is engaged with a body mouthpiece 802, thepatient's inspiratory effort creates a suction that forces the air totravel through the body bottom inlet 815 and the powder compartmentbottom inlet slit 806 inducing a bottom turbulent jet and simultaneouslythrough the body side opening windows 816 and the powder compartmentlateral vent 809 inducing a turbulent vortex confining the bottomturbulent jet, which generates a turbulent and swirling air flow pattern817 shown in FIG. 6d through the powder compartment. This flow allowsthe drug particles to be dispersed while minimizing powder retention andtravel through the powder compartment outlet 807 and into the bottominhalation channel 810, where the sharp geometric constriction of fluidpassage area allows further deagglomeration and break-up of the drugparticle clusters, and finally into the body inhalation channel 808 andthen into the mouth (or nose) and finally into the intended site oftreatment such as the nasal cavity or the lung. Additional supplementaryair flow is also provided to the body inhalation channel 808 through thebody side inlets 818 to provide additional dispersive forces as well asa comfortable inhalation and to maximize the entrainment capability ofthe air.

EXAMPLE

An inhaler embodiment according to the present invention has been testedin vitro to determine its aerodynamic profile as well as its powder dosedelivery characteristics. The inhaler embodiment comprised a powdercompartment according to the present invention that included one bottominlet slit and four lateral vents with pairs of lateral vents in offsetconfiguration as shown in FIG. 2f . The inhaler embodiment comprised abody inhalation channel bottom inlet, included in the top wall of thebody opening, including multiple orifices arranged to form a structuredgrid that jointly provided a sudden obstruction of channel passage areawhere the obstruction area was approximately 0.85 of the compartmentoutlet cross section area.

An experimental inhalation powder comprising inhalable amorphousspherical composite particles composed of 80% trehalose and 20% leucinewas produced by spray drying. The composite particle spry dried powderwas produced with a median particle size by volume (Dv50) ofapproximately 2 μm leading to high cohesiveness and adhesivenessproperties. The particle size, cohesive and adhesive properties of thepowder were representative of powders produced by spray drying forapplications of high dosage drug delivery to the lungs.

The inhaler was hand filled with 80 mg of composite particle spray driedpowder (40 mg per compartment), under controlled conditions oftemperature and relative humidity (T<25° C. and % RH<30%), inside aglove box conditioned with nitrogen and using an appropriate analyticalbalance. The inhaler was then tested at a flow rate of 42 litres perminute and at a pressure drop of 4 kPa on an Andersen cascade impactor(Graseby Andersen. Smyrna, Ga.), actuated once to allow a volume of 4litres of air to pass through the device, and the mass of powderdeposited at each stage of the cascade impactor was quantified usinggravimetric methods. From these data, the emitted mass and the fineparticle mass were calculated, where the emitted mass was the sum of allmasses collected from each of the impactor stages, including theinductor throat, and the fine particle mass was the mass of powdercollected below the 5 μm cut-off point. High dispersive andaerosolisation efficiency leads to a high emitted mass from the inhaler.In addition, the higher the fine particle mass, the higher the deliveredlung dose is expected to be. The results are summarized in the followingtable:

Delivery performance Emitted mass (EM) 73.4 mg Fine particle mass(FPM_(5μm)) 29.9 mg Fine particle fraction 40.7% (FPM_(5μm)/EM)

This data indicates that the inhaler embodiment according to the presentinvention is capable of effectively dispersing and delivering largedoses, in the range of 50 to 120 mg, of an inhalation powder, underinspiratory effort conditions which are compatible with the ability ofpatients.

The invention claimed is:
 1. A dry powder inhaler suitable for pulmonaryor nasal delivery, comprising an inhaler body and a cartridge; theinhaler comprising: (a) the inhaler body comprising a mouthpiece, abottom channel inlet, an inhalation channel for providing fluidcommunication between the patient's mouth when engaged with themouthpiece and the bottom channel inlet, at least one side inlet forallowing direct air admission from atmosphere into the inhalationchannel; an inhaler body opening formed therein and defined betweenopposing top and bottom walls and opposing side walls, said inhaler bodyopening having at least one open end by means of which the cartridge isinsertable into the opening and having at least one air inlet openingfor admitting air into the inhaler body opening, means for guidingmovement of the cartridge in the inhaler body opening relative to thebody and control the cartridge travel from a storage position into aninhalation position; wherein the cartridge; (b) the cartridge beingshaped for engagement in the inhaler body opening and having at leastone substantially cylindrical powder compartment formed therein forcarrying a powder-based medicament, and at least one air inlet vent; thepowder compartment having an outlet which allows fluid communicationwith the body inhalation channel through the body bottom channel inletand at least one pin for engaging with the body guiding movement means;wherein the cartridge is slidable within the body between the storageposition in which the at least one air inlet vent of the cartridge issubstantially sealed by the inhaler body such that there is no fluidcommunication to the cartridge, to the inhalation position, in which theor each air inlet vent of the cartridge is substantially aligned with anassociated air inlet opening of the inhaler body such that there isfluid communication between the inlet opening of the inhaler body, theor each air inlet vent of the cartridge, the cartridge top outlet andthe mouthpiece channel; wherein the cartridge having the at least oneinlet vent includes at least two air inlet vents, at least one of whichis a lateral air inlet vent and the inhaler body has an air inletopening associated with each of the air inlet vents of the cartridgewhich allow admission of air from the atmosphere into the cartridgepowder compartment when the cartridge is in the inhalation position; andthe inhaler body bottom channel inlet further comprising at least oneorifice which forms a sharp constriction in the fluid flow path from thecartridge powder compartment outlet into the inhalation channel when thepowder cartridge is moved into the inhalation position.
 2. The drypowder inhaler of claim 1, wherein the at least two air inlet vents ofthe cartridge includes a bottom inlet slit; and wherein the inhaler bodyincludes a bottom opening which aligns with the bottom inlet slit whenthe cartridge is in the inhalation position.
 3. The dry powder inhalerof claim 1, wherein the at least two air inlet vents of the cartridgeincludes at least one pair of lateral air vents formed in the side wallsof the cartridge: and wherein the air inlet openings of the inhaler bodyinclude at least one pair of side openings formed in the side walls ofthe body opening, each side opening aligning with at least oneassociated lateral air vent of the cartridge when the cartridge is inthe inhalation position.
 4. The dry powder inhaler of claim 3, whereinthe or each pair of lateral air vents are located on opposite sides ofthe compartment and the lateral air vents forming each pair are offsetrelative to each other so as to allow a non-tangential admission of air.5. The dry powder inhaler of claim 1, wherein each cartridge powdercompartment lateral vent has a width of between 0.1 and 2 mm.
 6. The drypowder inhaler of claim 5, wherein each cartridge powder compartmentlateral vent has a width of less than 1 mm.
 7. The dry powder inhaler ofclaim 1, wherein each side opening in the inhaler body is associatedwith a plurality of lateral vents.
 8. The dry powder inhaler of claim 1,wherein each cartridge powder compartment lateral vent tapers inwardstowards the inner surface of the compartment so as to funnel the air asit passes through the vent into the compartment.
 9. The dry powderinhaler of claim 1, wherein the inhaler body bottom channel inletincludes a plurality of orifices.
 10. The dry powder inhaler of claim 9,wherein said plurality of orifices are arranged to form a structuredgrid.
 11. The dry powder inhaler of claim 1, wherein cartridge powdercompartment includes a lateral protrusion in the area of the or each airinlet opening that provides mechanical contact and inference with top,bottom and side walls of the body opening when the cartridge is in thestorage position so as to seal each said air inlet opening.
 12. The drypowder inhaler of claim 1, wherein the inhaler body inhalation channelbottom inlet provides a geometric constriction in the fluid channelpassage area, the cross-sectional area of which constriction is between30% and 99% of the powder compartment outlet cross section area.
 13. Thedry powder inhaler of claim 12, wherein the cross-sectional area ofconstriction is between 80% and 98% of the powder compartment outletcross section area.